NONLINEAR PHARMACOKINETICS AND METABOLISM OF PACLITAXEL AND ITS PHARMACOKINETIC PHARMACODYNAMIC RELATIONSHIPS IN HUMANS/

Purpose: To characterize and model the disposition of paclitaxel in hu mans and define a pharmacodynamic relationships between paclitaxel dis position and its toxicity and efficacy. Patients and Methods: Paclitax el pharmacokinetics were studied in 55 courses of therapy in 30 patien ts. Paclitaxel wets administered at 135 mg/m(2) or 175 mg/m(2) by eith er a 3- or a 24-hour infusion schedule to patients with advanced ovari an cancer (n = 15), or at 225 mg/m(2) by 3-hour infusion to patients w ith advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpa clitaxel were quantified by high-performance liquid chromatography (HP LC). Pharmacokinetics were assessed by noncompartmental and model-depe ndent methods. Pharmacodynamic correlations were evaluated statistical ly and by regression models. Results: Paclitaxel disposition is nonlin ear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma dispo sition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multi-ple nonlinear processes. Neutropenia w as not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (C-max) . Neutropenia was related to the duration that plasma concentrations w ere greater than or equal to 0.05 mu mol/L, a relationship that is wel l described by a sigmoid maximum response (E(max)) model. Conclusion: The disposition of paclitaxel in humans is nonlinear, Paclitaxel metab olism to 6 alpha-hydroxylpaclitaxel is likely an important detoxificat ion pathway. Myelosuppression is related to the duration that plasma p aclitaxel concentrations are greater than or equal to 0.05 mu mol/L. T rials of new doses and schedules of paclitaxel should take into accoun t its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmac okinetic model should prove to be a powerful tool in predicting paclit axel disposition, regardless of dose and schedule, and should facilita te further pharmacodynamic investigations. (C) 1995 by American Societ y of Clinical Oncology.